Synthesis and Pharmacological Evaluation of New Chemical Entities from Ibuprofen as Novel Analgesic Candidates

Article abstract of DOI:10.1055/s-0034-1376976

Non-steroidal anti-inflammatory drugs (NSAIDs) are the first choice of drugs that are normally used for the treatment of pain and inflammation. Ibuprofen (I) and its analogues as the most widely used NSAIDs have been synthesized in recent years. In an effort to establish new candidates with improved analgesic properties, derivatives (II-VII) with substituted aromatic as well as aliphatic moieties were synthesized in this experiment and evaluated in formalin test with rats. The results were compared to ibuprofen and control groups. Findings indicated that derivatives with new alkylphenyl rings (VI and VII) had some similar or more analgesic activities relative to the control and ibuprofen groups, respectively; which could be justified as to more alkyl and phenyl groups instead of p-isobutylphenyl moiety in I.

Full text of DOI:10.1055/s-0034-1376976

Original Article 457
Synthesis and Pharmacological Evaluation of New
Chemical Entities from Ibuprofen as Novel Analgesic
Candidates
Authors
A. Ahmadi1, N. Naderi2, M. Daniali1, S. Kazemi1, S. Aazami1, N. Alizadeh1, B. Nahri-Niknafs1
Affiliations
1 Department of Chemistry, Faculty of Science, Karaj Branch, Islamic Azad University, Karaj, Iran
2 Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
Tehran, Iran
Key words
Abstract
well as aliphatic moieties were synthesized in
this experiment and evaluated in formalin test
with rats. The results were compared to ibupro-
fen and control groups. Findings indicated that
derivatives with new alkylphenyl rings (VI and
VII) had some similar or more analgesic activi-
ties relative to the control and ibuprofen groups,
respectively; which could be justified as to more
alkyl and phenyl groups instead of p-isobutyl-
phenyl moiety in I.
▶
NSAIDs
ibuprofen
analgesic
●
▼
▶
●
Non-steroidal anti-inflammatory drugs (NSAIDs)
are the first choice of drugs that are normally
used for the treatment of pain and inflamma-
tion. Ibuprofen (I) and its analogues as the most
widely used NSAIDs have been synthesized in
recent years. In an effort to establish new can-
didates with improved analgesic properties,
derivatives (II–VII) with substituted aromatic as
▶
●
▶
modified aromatic and
aliphatic moieties
●
Introduction
introduced to the market and gained an impres-
sive success. The serious cardiovascular effects
by some, however, caused the drugs to become
withdrawn from the market.
▼
During the last 3 decades the development of
non-steroidal anti-inflammatory drugs (NSAIDs)
has shown to be one of the major advancements
in chemotherapeutical research [1]. These agents
are among the most widely used drugs world-
wide and represent a mainstay in the therapy of
acute and chronic pain, fever and inflammation
by blocking the formation of Prostaglandins
(PGs). PGs are well-known as the mediators of
inflammation, pain and swelling. They are pro-
duced by the action of cyclooxygenase (COX)
enzyme on arachidonic acid. COX is the principal
target of NSAIDs. This enzyme exists as 2 iso-
forms of constitutive (COX-1) and inducible
(COX-2). COX-1 is constitutively expressed and
provides cytoprotection to the gastrointestinal
(GI) tract while COX-2 is inducible and mediates
inflammation. The traditional NSAIDs show
greater selectivity for COX-1 than COX-2 [2–4].
The NSAIDs’ use is frequently associated with a
broad spectrum of adverse effects of gastrointes-
tinal (GI), renal and hepatic which are usually
observed in patients undergoing long-term treat-
ment. Therefore, the development of new NSAIDs
without these side effects has long been awaited.
Selective COX-2 inhibitors that ‘coxib’ with better
safety profile have been marketed as the new
generation of these drugs which were rapidly
Producing effective NSAIDs with an improved
safety profile that eliminate the disadvantages of
selective COX-2 inhibitors and spare the gas-
trointestinal mucosa remains as a compelling
need. An alternative strategy to limit the risk of
GI damage induced by NSAIDs is to enhance the
protective mechanisms of the gastric mucosa
[5,6]. An important group of these drugs is the
class of 2-arylpropionic acids (Profen family)
which are able to reduce inflammation and pain.
Ibuprofen (2-p-isobutylphenyl propionic acid, I)
belongs to this class and uses to relieve the symp-
toms of a wide range of illness such as headache,
backache, period pain, dental pain, neuralgia,
rheumatic pain, muscular pain, migraine, cold
and flu symptoms and arthritis [5,7–10]. A broad
variety of this compound has been synthesized
with manifold synthetic methodologies [11–19]
but its prolonged usage (similar to other NSAIDs)
has been associated to gastrointestinal complica-
tions ranging from stomach irritation to life-threat-
ening GI ulceration bleeding and nephrotoxicity.
Therefore, the search for some brand new analgesic
and anti-inflammatory agents devoid of side effects
continues to be an active area of research in medic-
inalchemistry.Similarly, the synthetic approaches
received 17.04.2014
accepted 05.05.2014
Bibliography
DOI http://dx.doi.org/
10.1055/s-0034-1376976
Published online:
May 28, 2014
Drug Res 2015;
65: 457–462
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 2194-9379
Correspondence
Dr. A. Ahmadi, Associate
professor
Department of Chemistry
Faculty of Science
Islamic Azad University
P.O.Box: 31485-313
Karaj
Iran
Tel.: +98/26/34403 575
Fax: +98/26/34403 575
a-ahmadi@kiau.ac.ir
ahmadikiau@yahoo.com
Ahmadi A et al. New Chemical Entities from Ibuprofen… Drug Res 2015; 65: 457–462

458 Original Article
based upon chemical modification of I are investigated with the
aim of improving their safety profile [4,7,20–23].
In this research, the new analogues (II–V) with substituted
acidic side chain (without changing the acidic groups) similar to
13) (20.41mmol) at 0°C. Ethyl-2-(alkylsulphonyloxy) alkanoate
(6–10) was added to the cold solution portion-wise and the
mixture warmed to the room temperature. It was heated to 80°C
for 8h, cooled to room temperature, quenched with 5% HCl solu-
tion, extracted with ethyl acetate, dried over anhydrous Na2SO4
and concentrated under the reduced pressure to give the crude
compound ethyl 2-(4-alkylphenyl)-2-alkylalkanoate (14–20).
Finally, KOH (479mg, 8.55mmol) in 5ml of water was added to
a solution of 14–20 (7mmol) in 6ml of MeOH. The resultant
solution was stirred at room temperature for 4h. Methanol was
removed under reduced pressure, extracted with ethyl acetate,
acidified, water-washed, dried over anhydrous Na2SO4 and con-
centrated under the reduced pressure to give the desired com-
pounds 2-(4-alkylphenyl)-2-alkylalkanoic acid (II–VII).
▶
the substituted aryl moiety (VI and VII) were synthesized ( Fig.
●
1). The analgesic effects of these novel compounds were evalu-
ated in formalin (as a model of acute and chronic chemical pain)
test on rats and the results were compared to the ibuprofen (the
standard) and control (saline) groups.
Experimental
▼
Material and equipments
All chemicals were purchased from Merck and Aldrich Chemical
Companies. Melting points (uncorrected) were determined with
a digital Electro Thermal Melting Point apparatus (model 9100,
Electrothermal Engineering Ltd., Essex, UK). 1 H and 13C NMR
spectra were recorded with a Bruker 400MHz (AMX model, Karl-
sruhe, Germany) spectrometer. IR spectra were recorded with a
Thermo Nicolet FT-IR (Nexus-870 model, Nicolet Instrument Corp,
Madison, Wisconsin, USA) spectrophotometer. Mass spectra were
recorded with an Agilent Technologies 5973, Mass Selective
Detector (MSD) spectrometer (Wilmington, USA). Elemental
analyses were carried out with a Perkin-Elmer, CHN elemental
analyzer model 2400. Compound I was synthesized according to
a published method [24].
Compound II
Dark brown viscous liquid; Yield 51%; IR (KBr, νmax, cm−1):
2987, 1750, 1590, 1443, 1385, 1232, 946, 774; 1 H NMR spec-
trum in CDCl3 (δ, ppm): 0.82–1.96 (12H, m), 2.37–2.52 (1H, m),
3.13–4.02 (2H, m), 7–7.33 (4H, m); 13C{1 H}NMR spectrum in
CDCl3 (δ, ppm): 22.1, 27.4, 29.6, 44.1, 59.7, 126.2, 127.9, 129.2,
140.8, 179.2; Found (%): C, 76.43; H, 9.2; C14H20O2. Anal. calcd.
(%): C, 76.33; H, 9.15; Mass spectrum, m/z (Irel, %): 220 (51), 205
(6), 177 (20), 175 (100), 161 (12), 147 (16), 133 (57), 131 (60),
119 (70), 105 (36), 91 (66), 73 (60), 57 (56).
Compound III
Dark brown viscous liquid; Yield 48%; IR (KBr, νmax, cm−1):
2956, 1737, 1633, 1465, 1387, 1211, 1166, 1045, 872; 1 H NMR
spectrum in CDCl3 (δ, ppm): 0.9–0.99 (9H, m), 1.27–2.70 (9H,
m), 4.31–4.36 (1H, m), 6.99–7.3 (4H, m); 13C{1 H}NMR spectrum
in CDCl3 (δ, ppm): 13.9, 22.8, 28.1, 29.7, 30.3, 45.5, 76.6, 127.8,
129.4, 138.8, 146.7, 175.6; Found (%): C, 77.46; H, 9.78; C16H24O2.
Anal. calcd. (%): C, 77.38; H, 9.74; Mass spectrum, m/z (Irel, %):
248 (84), 205 (33), 192 (13), 191 (11), 175 (23), 161 (100), 148
(39), 145 (40), 131 (39), 117 (86), 105 (64), 91 (92).
▶
Preparations ( Fig. 2)
●
Compounds II–VII
To a solution of ethyl lactate, ethyl 2-hydroxyhexanoate, ethyl
2-hydroxyoctanoate, Ethyl mandelate or ethyl 2-hydroxy-2-
methylpropanoate (1–5) (8.47mmol) and triethylamine
(12.71mmol) in 15ml of dry dichloromethane was added por-
tion-wise MsCl (9.32mmol) at 0°C. The resultant mixture was
stirred at 0°C for an hour and left at room temperature for 2h.
After completion of the reaction, as indicated by TLC, the reac-
tion mixture was diluted with ethyl acetate, water-washed,
dried over anhydrous Na2SO4 and concentrated under reduced
pressuretogivethecrudecompoundethyl-2-(alkylsulphonyloxy)
alkanoate (6–10) which was used in the next step without any
purification. AlCl3 (10.20mmol) was added to isobutylbenzene,
Neopentylbenzene or 2,3-dimethyl-2,3-diphenyl butane (11–
Compound IV
Dark brown solid; m.p. 71°C; Yield 62%; IR (KBr, νmax, cm–1):
2956, 1736, 1574, 1412, 1376, 1265, 1168, 1020, 934, 875; 1
H
NMR spectrum in CDCl3 (δ, ppm): 0.8–0.86 (4H, m), 1.16–1.23
(9H, m), 1.47–2.49 (4H, m), 3.87–4.42 (5H, m), 5.02 (1H, m),
6.93–7.75 (4H, m); 13C{1 H}NMR spectrum in CDCl3 (δ, ppm):
Fig. 1 Structure formulas of 2-(p-isobutylphenyl)
C4H9
propionic acid (Ibuprofen, I), 2-(4-isobutylphenyl)-
COOH
COOH
2-methylpropanoic acid (II), 2-(4-isobutylphenyl)
COOH
hexanoic acid (III), 2-(4-isobutylphenyl) octanoic
acid (IV), 2-(4-isobutylphenyl)-2-phenylacetic acid
(V), 2-(4-neopentylphenyl) propanoic acid (VI),
2-(4-(2,3-dimethyl-3-phenylbutan-2-yl)phenyl)
propanoic acid (VII).
I
II
III
Ph
C6H13
COOH
COOH
COOH
V
IV
COOH
Ph
VII
VI
Ahmadi A et al. New Chemical Entities from Ibuprofen… Drug Res 2015; 65: 457–462

Original Article 459
Fig. 2 Synthesizing methods of final compounds
(I–VII) and their intermediates (6–10 and 14–20).
OMs
R2
OH
MsCl/Py
R1
COOEt
R1
COOEt
+
R2
R3
1–5
6–10
11–13
AlCl3
COOEt
R2
COOH
R2
H+
R1
R1
KOH / MeOH
R3
R3
I–VII
14–20
R1
CH3
CH3
C4H9
C6H13
Ph
R2
H
R3
Intermediates
6, 14
Final compounds
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Neopentyl
I
CH3
H
7, 15
II
8, 16
III
IV
V
H
9, 17
H
10, 18
6, 19
CH3
CH3
H
VI
VII
H
2,3-dimethyl-3-phenyl butyl
6, 20
13.9, 22, 24.6, 28.4, 31.2, 34, 40.3, 69.5, 76.6, 126.7, 128.1, 134.5,
140.1, 175.9; Found (%): C, 78.31; H, 10.26; C18H28O2. Anal.
calcd. (%): C, 78.21; H, 10.21. Mass spectrum, m/z (Irel, %): 276
(9), 233 (13), 205 (11), 191 (34), 175 (91), 161 (48), 147 (47), 131
(35), 117 (43), 105 (65), 91 (87), 57 (100).
Compound VII
Light brown solid; m.p. 122°C; Yield 52%; IR (KBr, νmax, cm–1):
2975, 1707, 1599, 1496, 1442, 1379, 1223, 1029, 974, 774; 1
H
NMR spectrum in CDCl3 (δ, ppm): 1.3 (15H, m), 4.24–4.28 (1H,
m), 6.82–7.62 (9H, m); 13C{1 H}NMR spectrum in CDCl3 (δ,
ppm): 25.7, 29, 30.6, 44.2, 126.2, 127.4, 128.2, 129.2, 132.4,
147.5, 152.1, 205.9; Found (%): C, 81.35; H, 8.49; C21H26O2. Anal.
calcd. (%): C, 81.25; H, 8.44; Mass spectrum, m/z (Irel, %): 310 (5),
295 (5), 265 (16), 277 (8), 251 (16), 237 (32), 221 (16), 209 (12),
195 (16), 181 (16), 159 (18), 145 (20), 133 (24), 119 (100), 105
(60), 91 (90), 77 (13), 57 (8).
Compound V
Dark brown viscous liquid; Yield 51%; IR (KBr, νmax, cm–1): 2965,
1724, 1570, 1460, 1362, 1245, 1184, 935, 718; 1 H NMR spec-
trum in CDCl3 (δ, ppm): 0.87–1.27 (6H, m), 2.44–2.46 (1H, m),
3.41–4.21 (3H, m), 5.37 (1H, m), 7.21–7.5 (9H, m); 13C{1 H}NMR
spectrum in CDCl3 (δ, ppm): 14.1, 22.4, 22.6, 29.7, 30.4, 45, 52.8,
127.9, 129.3, 135.5, 140.9, 178.2; Found (%): C, 80.64; H, 7.55;
C18H20O2. Anal. calcd. (%): C, 80.56; H, 7.51; Mass spectrum, m/z
(Irel, %): 268 (97), 223 (100), 225 (97), 207 (8), 191 (8), 181 (78),
167 (72), 165 (95), 145 (31), 133 (14), 115 (15), 105 (34), 91 (43),
77 (24), 57 (24).
Animals
53 adult male wistar rats (Pasteur Institute, Tehran, Iran) weigh-
ing 220±20g at the beginning of the experiment were randomly
housed 4 per cage in a temperature-controlled colony room
under the 12h light/dark cycle. Animals were given free access
to water and standard laboratory rat chow (Pars Company,
Tehran, Iran). All behavioral experiments were carried out
between 9am–4pm under the normal room light and at 25°C.
This study was carried out in accordance with the guidelines set
forth in the Guide for the Care and Use of Laboratory Animals
(NIH) and those in the Research Council of Shahid Beheshti Uni-
versity of Medical Sciences, Tehran, Iran.
Compound VI
Dark brown viscous liquid; Yield 41%; IR (KBr, νmax, cm–1): 2952,
1708, 1604, 1461, 1414, 1364, 1236, 1077, 938, 726; 1 H NMR
spectrum in CDCl3 (δ, ppm): 0.88–0.98 (9H, m), 1.37–1.44 (3H,
m), 2.48–2.81 (2H, m), 3.39–3.73 (1H, m), 7.05–7.26 (4H, m);
13C{1 H}NMR spectrum in CDCl3 (δ, ppm): 15.6, 29.2, 30.6, 45.6,
50.5, 129.7, 130.4, 132.8, 141.5, 175.9; Found (%): C, 76.42; H,
9.20; C14H20O2. Anal. calcd. (%): C, 76.33; H, 9.15; Mass spec-
trum, m/z (Irel, %): 220 (23), 191 (5), 178 (20), 164 (90), 119 (84),
105 (9), 91 (44), 71 (19), 57 (100).
The formalin test
Rats were pretreated with the test compounds or vehicle (con-
trol group) 30min before the initiation of the pain test. The test
compounds were dissolved in DMSO. The volume of injection
was 10ml/kg. In the treatment groups, ibuprofen and their
Ahmadi A et al. New Chemical Entities from Ibuprofen… Drug Res 2015; 65: 457–462

460 Original Article
derivatives were administered intraperitoneally (i.p.) at the
Discussion
dose of 100mg/kg [24,25]. The control group received DMSO. As
the pain test, formalin solution (40µl, 5%) was subcutaneously
injected into the dorsal surface of rat hind paws. Then the ani-
mals were placed in a Plexiglas chamber (30×30×30cm3), with
a mirror at 45° angle underneath for unobstructed observation.
The pain-related behavior of the every rat was observed for the
next 60min. The behaviors were quantified as described by
Dubuisson and Dennis [26] (0=normal weight bearing on the
injected paw, 1=limping during locomotion or resting the paw
lightly on the floor, 2=elevation of the injected paw so that at
most the nails touch the floor, and 3=licking, biting or shaking
the injected paw). Subjects’ behaviors were continuously scored
in 5min intervals by a trained observer who was kept blind to
every subject’s treatment condition. The area under the curve of
the pain score against time was calculated for individual rats.
▼
Different chemical structures of 2-arylpropionic acids (main
family of NSAIDs) have been found to show different analgesic
and anti-inflammatory activities. The main structural features
of these compounds may be considered in terms of 3 basic units:
(i) the acidic side chain; (ii) the central aryl moiety; and (iii) a
hydrophobic terminal residue [27,28]. To develop brand new
compounds which are biologically effective but devoid of side
effects inherent in the traditional NSAIDs, several strategies
have been reported to modify the well-known nonselective
NSAIDs (such as ibuprofen). Most studies report the derivatiza-
tion of the carboxylic acid to amide groups increased anti-
inflammatory activities with reduced ulcerogenic potential [29]
which is usually related to their potent inhibitory activity against
COX-2 but not COX-1.
It also seems that the derivatives with modified aryl or hydro-
phobic terminal moieties through maintaining the acidic group
show the potent inhibitory activities against COX-1 and produce
more analgesic compounds [23,30]. It may concern to binding
the carboxyl group to the COX at the binding site of the arachi-
donic acid [31]. Moreover, the comparison between 2 substi-
tuted I alkanoic acids analogues (arylacetic and arylpropionic
derivatives) show that more analgesic activities are obtained
when the number and branching of carbons’ chain increase [22].
In this study, to achieve the potent analgesic analogues, some
structural modification of I were done and the brand new com-
pounds were synthesized by replacing 2-propaonic acid with
various alkanoic (methyl, hexanoic, octanoic and phenyl acetic)
acids similar to changing p-isobutylphenyl moiety by various
alkylphenyl (p-neoupentylphenyl and 2,3-dimethyl-2,3-diphe-
nylbutane) rings. The results indicated that the derivatives with
new alkylphenyl rings (VI and VII) showed similar or more anal-
gesic activity compared to the control and ibuprofen groups
respectively; which could be the result of more alkyl and phenyl
groups instead of p-isobutylphenyl moiety in I. As it had been
shown previously [23], the existence of more phenyl group in
aryl moiety of the molecule could produce more analgesic drugs
(e.g., ketoprofen, and naproxen). Consequently, more phenyl
ring was added to this side with additional substituted alkyl
groups (VII) for obtaining better analgesic activities relative to
the control and ibuprofen groups. The analogues with additional
substituted alkyl without phenyl groups (VI) showed similar
analgesic activity to I. It proved the important effects of more
phenyl ring on analgesic activity in this side of the molecule.
All new brand analogues (II–V) exhibited more analgesic activi-
ties compared to the control group but less than I that supported
the substituted alkanoic acids derivatives could not improve the
antinociception properties. In addition, relative to substituted
alkanoic acids derivatives together, the reported results con-
firmed that increasing the carbon number in alkyl (III and IV) or
phenyl (V) groups might cause adverse effects on analgesic
activity and the higher steric hindrance of substituted acidic
chain in II that may produce lower analgesic activity than other
drugs.
Statistical analysis
Data were presented as means±S.E.M. Statistical analysis was
conducted with Graphpad Prism software, Version 5. Compari-
sons were carried out using one-way Analysis of Variance
(ANOVA) followed by Dunnett’s post test. A p-value less than
0.05 was considered as the level of significance.
Results
▼
Chemistry
The synthetic strategy of the title compounds was outlined in
▶
●
the
Fig. 2. Ethyl-2-(alkylsulphonyloxy) alkanoates (6–10)
were prepared according to the published method [24] using
ethyl 2-hydroxyalkanoates and mesyl chloride (MsCl) in dry
dichloromethane. Reaction of these intermediates with a mix-
ture of various alkylbenzenes and AlCl3 yielded ethyl
2-(4-alkylphenyl)-2-alkylalkanoates (14–20) was examined.
Finally the desired drugs (I–VII) were prepared with these inter-
mediates reacting to KOH in MeOH and acidifying the ester
products. In this research, 2-propanoic acid moiety was replaced
by substituted alkyl and phenyl acids for obtaining II–V. Also
isobutylbenzene was replaced by neopentylbenzene and
2,3-dimethyl-2,3-diphenyl butane for investigating the alkyl and
phenyl increase in the hydrophobic terminal chain on the cen-
tral aryl moiety of the molecule in analgesic activities of VI and
VII. Spectroscopic (IR, 1 H and 13C-NMR, Mass) and elemental
(CH) data confirmed the structure of the newly synthesized
compounds. The purity of every compound was checked by TLC
with ethyl acetate-hexane as the eluent.
Pharmacology
Analgesic activity of ibuprofen and its newly synthesized
derivatives in formalin test
One-way ANOVA revealed a significant change in the AUC of pain
score between groups [F(7,45)=3.83, p=0.0024; Fig. 3. Fur-
ther analysis in Dunnett’s multiple comparison post test showed
that ibuprofen (I) and compound VII (p<0.01) at the dose of 100
mg/kg significantly decreased pain score in formalin test com-
paring to the control (DMSO) group. Also, rats treated with com-
pound VI showed a significantly lower pain score compared
with the control group (p<0.05). Other derivatives (II–V) did not
show any significant analgesic activity relative to the control
group.
▶
●
Conclusion
▼
It can be concluded that changing the acidic side chain of ibu-
profen with more alkyl chains was not an effective factor for
decreasing pain relative to I in acute and chronic pain. Improve-
Ahmadi A et al. New Chemical Entities from Ibuprofen… Drug Res 2015; 65: 457–462

Original Article 461
Fig. 3 The analgesic effects of ibuprofen (I) and
100
80
60
40
20
0
its derivatives (II–VII) on pain related behavior of
rats in Formalin test. Pain scores were recorded
based on method described by Dubuisson and
Dennis [26] during 60min before the formalin (5%;
40μL) injection into the rat hind paws (left panels).
The area under the curve (AUC) of pain scores for
each group was depicted (right panels). Data were
mean±SEM of 6–7 rats in each group. *p<0.05,
**p<0.01 significant difference compared with
the control (DMSO) group.
**
*
**
CTL
I
II
III
IV
V
VI
VII
100
2.5
2.0
1.5
1.0
0.5
0.0
Control
I
II
80
60
40
20
0
*
0
5
10 15 20 25 30 35 40 45 50 55 60
CTL
I
II
Time (min)
100
80
60
40
20
0
2.5
2.0
1.5
1.0
0.5
0.0
Control
I
*
III
0
5
10 15 20 25 30 35 40 45 50 55 60
Time (min)
CTL
I
III
100
80
60
40
20
0
2.5
2.0
1.5
1.0
0.5
0.0
Control
I
**
IV
0
5
10 15 20 25 30 35 40 45 50 55 60
Time (min)
CTL
I
IV
100
80
60
40
20
0
2.5
2.0
1.5
1.0
0.5
0.0
Control
I
V
*
0
5
10 15 20 25 30 35 40 45 50 55 60
Time (min)
CTL
I
V
**
VI
100
80
60
40
20
0
2.5
2.0
1.5
1.0
0.5
0.0
Control
I
VI
**
0
5
10 15 20 25 30 35 40 45 50 55 60
Time (min)
CTL
I
100
80
60
40
20
0
2.5
2.0
1.5
1.0
0.5
0.0
Control
I
**
VII
**
0
5
10 15 20 25 30 35 40 45 50 55 60
CTL
I
VII
Time (min)
Ahmadi A et al. New Chemical Entities from Ibuprofen… Drug Res 2015; 65: 457–462

462 Original Article
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Acknowledgements
▼
This article is a report made out a research project that enjoyed
the financial supports of INSF (Iran National Science Foundation)
and conducted at Karaj Branch, Islamic Azad University, Iran.
The authors thank appreciate Dr. Natasha Pourdana, the certified
editor in Journal of Language Education in Asia (LEiA), for proof-
reading the initial draft of this article.
18 Guo CB, Cai ZF, Guo ZR et al. Design, Synthesis and in vitro Evaluation
of Thiazole Derivatives of Ibuprofen as Cyclooxygenase-2 Inhibitors.
Chinese Chem Lett 2006; 17: 325–328
Conflict of Interest
19 Uludag MO, Caliskan Ergun B, Alkan DA et al. Stable ester and amide
conjugates of some NSAIDs as analgesic and antiinflammatory com-
pounds with improved biological activity. Turk J Chem 2011; 35:
427–439
▼
Authors declare no conflict of interests.
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